The present invention relates to compositions and methods for the treatment or prophylaxis of sepsis or septic shock. In a particular aspect, the invention relates to compositions and methods which, in addition to treating the underlying bacterial infection, also alleviate disturbances in the hemostatic system that contribute to septic shock.
Sepsis occurs primarily in hospitalized patients who usually have underlying diseases that render them susceptible to bloodstream invasion. In most cases of sepsis, the predominant pathogen is Escherichia coli, followed by the Klebsiella-Enterobacter-Serratia group and then Pseudomonas. The genitourinary tract is the most common site of infection, the gastrointestinal tract and respiratory tract being the next most frequent sources of sepsis. Other common foci are wound, burn, and pelvic infections and infected intravenous catheters.
Gram-negative bacteria have become the leading cause of fatal bacterial infections in hospital patients. The mortality rate for patients suffering from Gram-negative bacteremia has approached forty percent in the past twenty years, despite the use of antibiotics and aggressive support techniques. These bacteria are distinguished by a membrane that is relatively impermeable to drugs and by an endotoxin produced by all Gram-negative bacteria which remains lethally toxic, even after the bacterial cells have been killed. The lethality of Gram-negative infections thus is due both to uncontrolled growth of the viable bacteria and to the release of endotoxin.
Endotoxins, which are of great structural diversity and unique to Gram-negative bacteria, are associated with the lipopolysaccharide ("LPS") component of the outer membrane of the bacterial cells. The LPS from different bacterial species are structurally similar.
A serious consequence of Gram-negative bacteremia often is septic shock. Septic shock is characterized by inadequate tissue perfusion, leading to insufficient oxygen supply to tissues, hypotension and oliguria. Septic shock occurs because bacterial products, principally LPS, react with cell membranes and components of the coagulation, complement, fibrinolytic and bradykinin systems to activate coagulation, injure cells and alter blood flow, especially in the capillaries. The various effects of microbial infection on the hemostatic system are illustrated schematically in FIG. 1 of the drawings. Microorganisms frequently activate the classic complement pathway, and endotoxin activates the alternate pathway. Complement activation, leukotriene generation and the direct effects of endotoxin on neutrophils lead to accumulation of these inflammatory cells in the lungs, release of their enzymes and production of toxic oxygen radicals which damage the pulmonary endothelium and initiate the acute respiratory distress syndrome ("ARDS"). ARDS is a major cause of death in patients with septic shock and is characterized by pulmonary congestion, granulocyte aggregation, haemorrhage and capillary thrombi.
Activation of the coagulation system results in thrombin generation and platelet thrombi formation in the microcirculation in many tissues. The pathogenesis of this syndrome involves the activation of the intrinsic coagulation system by factor XII. Activated factor XII initiates the intrinsic coagulation cascade and eventually fibrinogen is converted to fibrin and clotting occurs. Uncontrolled activation of coagulation, usually accompanied by shock, will result in thrombosis and consumption of clotting factors II, V, and VIII. Some common complications of disseminated intravascular coagulation are severe clinical bleeding, thrombosis, tissue ischaemia and necrosis, haemolysis and organ failure.
At the same time, as coagulation is apparently initiated by endotoxin, countervening mechanisms also appear to be activated by clotting, namely activation of the fibrinolytic system. Activated factor XII converts plasminogen pro-activator to plasminogen activator which subsequently converts plasminogen to plasmin thereby mediating clot lysis. The activation of plasma fibrinolytic systems may therefore also contribute to bleeding tendencies.
Endotoxemia is associated with an increase in the circulating levels of tissue plasminogen activator inhibitor ("PAI"). This inhibitor rapidly inactivates tissue plasminogen activator ("tPA"), thereby hindering its ability to promote fibrinolysis through activation of plasminogen to plasmin. Impairment of fibrinolysis may cause fibrin deposition in blood vessels, thus contributing to the disseminated intravascular coagulation associated with septic shock.
Disseminated intravascular coagulation is not a complication exclusive to gram-negative infections. It has also been observed in gram-positive, fungal, and viral infections.
In view of the limited effectiveness of antibiotics in treating Gram-negative bacteremia, efforts have been made to use antibody preparations to combat Gram-negative bacterial infections. Studies have shown that intravenous preparations of polyclonal immunoglobulins can be effective in decreasing the incidence of opportunistic nosocomial Gram-negative bacterial infections, especially in immunocompromised patients. Although the polyclonal immunoglobulin is effective in killing the bacterial organisms, such preparations have proved to be generally unsatisfactory in treating septic shock.
Copending U.S. patent application Ser. No. 257,445, filed Oct. 12, 1988 and assigned to the same assignee as the present application, discloses compositions for use in the prophylaxis or treatment of Gram-negative bacteremia or endotoxic shock. These compositions comprise a combination of human polyclonal immunoglobulins containing antibodies against antigens of Gram-negative bacteria and monoclonal antibodies which are specific for epitopes common to the lipid A moiety of the lipopolysaccharides of a variety of Gram-negative bacteria. The disclosure of that application is incorporated herein by reference. The compositions described in the copending application have been found very useful for treating the underlying bacterial infection and for preventing or lessening the severity of septic shock.
It has been suggested that the plasma protein, known as protein C, plays a natural role in the defense against Gram-negative bacterial infections. See Taylor et al., J. Clin. Invest., 79, 918-925 (1987). The authors of this article demonstrated that, in animals infused with live cultures of E. coli, high doses of activated protein C could function as an effective in vivo anticoagulant and could protect the animals against the lethal effects of the bacteria. Although protection against Gram-negative bacteria was demonstrated by Taylor et al., very high doses of protein C were required. Moreover, protein C does not affect the underlying bacterial infection, but only the hemostatic disturbances associated with the infection. In a recent presentation at the 61st Annual Meeting of the American Heart Association on Nov. 15, 1988, Taylor suggested that the dosage of protein C for treating bacteria-related coagulation disorders might be reduced by using it in combination with protein S and a monoclonal antibody to tissue factor. The feasibility of such an approach has not yet been established.
Accordingly, a need exists for compositions and methods for the treatment or prophylaxis of Gram-negative bacteremia and septic shock, which are effective against both the underlying infection and the widespread intravascular clotting which accompanies the disease.